Unraveling the potential role of DHHCs-mediated protein S-palmitoylation in cancer biology through untargeted metabolomics and in silico approaches

Abstract

Introduction: Protein S-palmitoylation in cancer: Protein S-palmitoylation is a reversible protein lipidation in which a thioester bond is formed between a cysteine (Cys) residue of a protein and a 16-carbon fatty acid chain. This modification is catalyzed by palmitoyl acyl transferases, also known as the DHHCs, because of their Asp-His-His-Cys (DHHC) catalytic motif [1]. Deregulation of DHHC enzymes has been linked to various diseases, including cancer and various infections [2, 3]. Cancer, a major cause of global mortality, is characterized by features like uncontrolled cell growth, resistance to cell death, angiogenesis, invasion, and metastasis [4]. Several of these processes are controlled by DHHC-mediated S-palmitoylation of oncogenes or tumor suppressors, including growth factor receptors (e.g., epidermal growth factor receptor; EGFR), kinases (e.g., protein kinase B; AKT), and transcription factors (e.g., β-catenin) [5, 6]. Given the critical role of S-palmitoylation in cancer, targeting the enzymes involved in this modification and the palmitoylated proteins themselves represents a promising therapeutic strategy.